Dry powder inhalers (“DPIs”) represent a promising alternative to pressurized meted dose inhaler (“pMDI”) devices for delivering drug aerosols without using CFC propellants. See generally, Crowder et al., 2001: an Odyssey in Inhaler Formulation and Design, Pharmaceutical Technology, pp. 99-113, July 2001; and Peart et al., New Developments in Dry Powder Inhaler Technology, American Pharmaceutical Review, Vol. 4, n,3, pp. 37-45 (2001). Martonen et al. 2005 Respiratory Care, Smyth and Hickey American Journal of Drug Delivery, 2005.
Typically, the DPIs are configured to deliver a powdered drug or drug mixture that includes an excipient and/or other ingredients. Conventionally, many DPIs have operated passively, relying on the inspiratory effort of the patient to dispense the drug provided by the powder. Unfortunately, this passive operation can lead to poor dosing uniformity since inspiratory capabilities can vary from patient to patient, and sometimes even use-to-use by the same patient, particularly if the patient is undergoing an asthmatic attack or respiratory-type ailment which tends to close the airway.
Generally described, known single and multiple dose DPI devices use: (a) individual pre-measured doses, such as capsules containing the drug, which can be inserted into the device prior to dispensing; or (b) bulk powder reservoirs which are configured to administer successive quantities of the drug to the patient via a dispensing chamber which dispenses the proper dose. See generally, Prime et al., Review of Dry Powder Inhaler's, 26 Adv. Drug Delivery Rev., pp. 51-58 (1997); and Hickey et al., A New Millennium for Inhaler Technology, 21 Pharm. Tech., n. 6, pp. 116-125 (1997).
In operation, DPI devices desire to administer a uniform aerosol dispersion amount in a desired physical form (such as a particulate size) of the dry powder into a patient's airway and direct it to a desired deposit site. If the patient is unable to provide sufficient respiratory effort, the extent of drug penetration, especially to the lower portion of the airway, may be impeded. This may result in premature deposit of the powder in the patient's mouth or throat.
A number of obstacles can undesirably impact the performance of the DPI. For example, the small size of the inhalable particles in the dry powder drug mixture can subject them to forces of agglomeration and/or cohesion (i.e., certain types of dry powders are susceptible to agglomeration, which is typically caused by particles of the drug adhering together), which can result in poor flow and non-uniform dispersion. In addition, as noted above, many dry powder formulations employ larger excipient particles to promote flow properties of the drug. However, separation of the drug from the excipient, as well as the presence of agglomeration, can require additional inspiratory effort, which, again, can impact the stable dispersion of the powder within the air stream of the patient. Unstable dispersions may inhibit the drug from reaching its preferred deposit/destination site and can prematurely deposit undue amounts of the drug elsewhere.
A number of different inhalation devices have been designed to attempt to resolve problems attendant with conventional passive inhalers. For example, U.S. Pat. No. 5,655,523 discloses and claims a dry powder inhalation device which has a deagglormeration-aerosolization plunger rod or biased hammer and solenoid. U.S. Pat. No. 3,948,264 discloses the use of a battery-powered solenoid buzzer to vibrate the capsule to effectuate the efficient release of the powder contained therein. Those devices are based on the proposition that the release of the dry powder can be effectively facilitated by the use of energy input independent of patient respiratory effort.
U.S. Pat. No. 5,533,502 to Piper discloses and claims a powder inhaler using patient inspiratory efforts for generating a respirable aerosol. The Piper invention also includes a cartridge capable of rotating, holding the depressed wells or blisters defining the medicament holding receptacles. A spring-loaded carriage compresses the blister against conduits with sharp edges that puncture the blister to release the medication that is then entrained in air drawn in from the air inlet conduit so that aerosolized medication is emitted from the aerosol outlet conduit.
Crowder et al. describe a dry powder inhaler in U.S. Pat. No. 6,889,690 comprising a piezoelectric polymer packaging in which the powder for aerosolization is simulated using non-linear signals determined a priori for specific powders.
In recent years, dry powder inhalers (DPIs) have gained widespread use, particularly in the United States. Currently, the DPI market is estimated to be worth in excess of $4 billion. Dry powder inhalers have the added advantages of a wide range of doses that can be delivered, excellent stability of drugs in powder form (no refrigeration), ease of maintaining sterility, non-ozone depletion, and they require no press-and-breathe coordination.
There is great potential for delivering a number of therapeutic compounds via the lungs (see, for example, Martonen T., Smyth H D C, Isaccs K., Burton R., “Issues in Drug Delivery: Dry Powder Inhaler Performance and Lung Deposition”: Respiratory Care. 2005, 50(9); and Smyth H D C, Hickey, A J, “Carriers in Drug Powder Delivery: Implications for Inhalation System Design,” American Journal of Drug Delivery, 2005, 3(2), 117-132). In the search for non-invasive delivery of biologics (which currently must be injected), it was realized that the large highly absorptive surface area of the lung with low metabolic drug degradation, could be used for systemic delivery of proteins such as insulin. The administration of small molecular weight drugs previously administered by injection is currently under investigation via the inhalation route either to provide non-invasive rapid onset of action, or to improve the therapeutic ratio for drugs acting in the lung (e.g. lung cancer).
Gene therapy of pulmonary disease is still in its infancy but could provide valuable solutions to currently unmet medical needs. The recognition that the airways may provide a real opportunity for delivering biotech therapeutics in a non-invasive way was recently achieved with Exubera™, an inhaled insulin product. This product has obtained a recommendation for approval by US Food and Drug Administration and will lead to expanded opportunities for other biologics to be administered via the airways.
Key to all inhalation dosage forms is the need to maximize the “respirable dose” (particles with aerodynamic diameters <5.0 μm that deposit in the lung) of a therapeutic agent. However, both propellant-based inhalers and current DPI systems only achieve lung deposition efficiencies of less than 20% of the delivered dose. The primary reason why powder systems have limited efficiency is the difficult balancing of particle size (particles under 5 μm diameter) and strong inter-particulate forces that prevent deaggregation of powders (strong cohesive forces begin to dominate at particle sizes <10 μm) (Smyth H D C., Hickey, A J., “Carriers in Drug Powder Delivery: Implications for inhalation System Design,” American Journal of Drug Delivery, 2005, 3(2), 117-132). Thus, DPIs require considerable inspiratory effort to draw the powder formulation from the device to generate aerosols for efficient lung deposition (see FIG. 1 for an illustration of typical mechanism of powder dispersion for DPIs). Many patients, particularly asthmatic patients, children, and elderly patients, which are important patient groups for respiratory disease, are not capable of such effort. In most DPIs, approximately 60 L/min of airflow is required to effectively deaggregate the fine cohesive powder. All currently available DPIs suffer from this potential drawback.
Multiple studies have shown that the dose emitted from dry powder inhalers (DPI) is dependent on air flow rates (see Martonen T., Smyth H D C, Isaccs K., Burton R., “Issues in Drug Delivery: Dry Powder Inhaler Performance and Lung Deposition”: Respiratory Care. 2005, 50(9)). Increasing air-flow increases drug dispersion due to increases in drag forces of the fluid acting on the particle located in the flow. The Turbuhaler® device (a common DPI), is not suitable for children because of the low flow achieved by this patient group (see Martonen T., Smyth H D C, Isaccs K., Burton R., “Issues in Drug Delivery: Dry Powder Inhaler Performance and Lung Deposition”: Respiratory Care. 2005, 50(9)).
Considerable intra-patient variability of inhalation rates has been found when patients inhale through two leading DPI devices. That inherent variability has prompted several companies to evaluate ways of providing energy in the inhaler (i.e. “active” DPIs). Currently, there is no active DPI commercially available. The active inhalers under investigation include technologies that use compressed air, piezoelectric actuators, and electric motors. The designs of those inhalers are very complex and utilize many moving parts and components. The complexity of those devices presents several major drawbacks including high cost, component failure risk, complex manufacturing procedures, expensive quality control, and difficulty in meeting specifications for regulatory approval and release (Food and Drug Administration).
Alternatively, powder technology provides potential solutions for flow rate dependence of DPIs. For example, hollow porous microparticles having a geometric size of 5-30 μm, but aerodynamic sizes of 1-5 μm require less power for dispersion than small particles of the same mass. This may lead to flow independent drug dispersion but is likely to be limited to a few types of drugs with relevant physicochemical properties.
Thus there are several problems associated with current dry powder inhaler systems including the most problematic issue: the dose a patient receives is highly dependent on the flow rate the patient can draw through the passive-dispersion device. Several patents describing potential solutions to this problem employ an external energy source to assist in the dispersion of powders and remove this dosing dependence on patient inhalation characteristics. Only one of these devices has made it to market or been approved by regulatory agencies such as the U.S. Food and Drug Administration. Even upon approval, it is likely that these complex devices will have significant costs of manufacture and quality control, which could have a significant impact on the costs of drugs to patients.
The present disclosure describes exemplary dry powder inhalers and associated single or multi-dose packaging, which holds the compound to be delivered for inhalation as a dry powder. These dry powder inhalers bridge the gap between passive devices and active devices. The inhalers are passive devices that operate using the energy generated by the patient inspiratory flow inhalation maneuver. However, the energy generated by airflow within the devices is focused on the powder by using oscillations induced by airflow across an aeroelastic element. In this way the inhalers can be “tuned” to disperse the powder most efficiently by adjusting the resonance frequencies of the elastic element to match the physicochemical properties of the powder. In addition, the airflow rate required to generate the appropriate oscillations within the device is minimized because some of the energy used to create the vibrations in the elastic element is pre-stored in the element in the form of elastic tension (potential energy). Inhaler performance may be tailored to the lung function of individual patients by modulating the elastic tension. Thus, even patients with poor lung function and those who have minimal capacity to generate airflow during inspiration will able to attain the flow rate required to induce oscillations in the elastic element.